An Antibody-Drug Conjugate Directed against Lymphocyte Antigen 6 Complex, Locus E (LY6E) Provides Robust Tumor Killing in a Wide Range of Solid Tumor Malignancies.

Abstract

PURPOSE:

Chemotherapies are limited by a narrow therapeutic index resulting in suboptimal exposure of the tumor to the drug and acquired tumor resistance. One approach to overcome this is through antibody-drug conjugates (ADC) that facilitate greater potency via target-specific delivery of highly potent cytotoxic agents.

EXPERIMENTAL DESIGN:

In this study, we used a bioinformatics approach to identify the lymphocyte antigen 6 complex locus E (LY6E), an IFN-inducible glycosylphosphatidylinositol (GPI)-linked cell membrane protein as a promising ADC target. We developed a monoclonal anti-LY6E antibody and characterized in situ LY6E expression in over 750 cancer specimens and normal tissues. Target-dependent anti-LY6E ADC killing was investigated both in vitro and in vivo using patient-derived xenograft models.

RESULTS:

Using in silico approaches, we found that LY6E was significantly overexpressed and amplified in a wide array of different human solid tumors. IHC analysis revealed high LY6E protein expression in a number of tumor types, such as breast, lung, gastric, ovarian, pancreatic, kidney and head/neck carcinomas. Characterization of the endocytic pathways for LY6E revealed that the LY6E-specific antibody is internalized into cells leading to lysosomal accumulation. Consistent with this, a LY6E-specific ADC inhibited in vitro cell proliferation and produced durable tumor regression in vivo in clinically relevant LY6E-expressing xenograft models.

CONCLUSIONS:

Our results identify LY6E as a highly promising molecular ADC target for a variety of solid tumor types with current unmet medical need.

• Authors: Jyoti Asundi, Lisa Crocker, Jarrod Tremayne, Peter Chang, Chie Sakanaka, Josh Tanguay, Susan Spencer, Sreedevi Chalasani, Elizabeth Luis, Karen Gascoigne, Rupal Desai, Rajiv Raja, Brad A Friedman, Peter M Haverty, Paul Polakis, Ron Firestein
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 14 Pg. 3252-62 (Jul 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25862760 (Publication Type: Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antigens, Neoplasm
• Antigens, Surface
• Antineoplastic Agents
• GPI-Linked Proteins
• Immunoconjugates
• LY6E protein, human
• RNA, Small Interfering

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antigens, Neoplasm (immunology, pharmacology)
• Antigens, Surface (immunology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Flow Cytometry
• GPI-Linked Proteins (immunology)
• Humans
• Immunoblotting
• Immunoconjugates (pharmacology)
• Immunohistochemistry
• Mice
• Mice, SCID
• Neoplasms (immunology)
• Polymerase Chain Reaction
• RNA, Small Interfering
• Transfection
• Xenograft Model Antitumor Assays